Alzheimer-Type Cerebral Amyloidosis in the Context of HIV Infection: Implications for a Proposed New Treatment Approach.

Reverse transcriptase inhibitors (RTIs) are currently broadly prescribed for the treatment of HIV infection but are also thought to prevent Alzheimer's disease (AD) progression by protecting against amyloidosis. Our study evaluates the hypothesis that reverse transcriptase inhibitors protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection. We compiled a case series of participants from a prospective study of the neurological consequences of HIV infection at the HIV Neurobehavioral Research Program (HNRP) who had serial neuropsychological and neurological assessments and were on RTIs. Two participants had gross and microscopic examination and immunohistochemistry of the brain at autopsy; one was assessed clinically for Alzheimer's disease by cerebrospinal fluid (CSF) analysis of phosphorylated-Tau, Total-Tau and Aß42. Additionally, a larger cohort of 250 autopsied individuals was evaluated for presence of amyloid plaques, Tau, and related pathologies. Three older, virally suppressed individuals with HIV who had long-term treatment with RTIs were included in analyses. Two cases demonstrated substantial cerebral amyloid deposition at autopsy. The third case met clinical criteria for AD based on a typical clinical course and CSF biomarker profile. In the larger cohort of autopsied individuals, the prevalence of cerebral amyloidosis among people with HIV (PWH) was greater for those on RTIs. Our study showed that long-term RTI therapy did not protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection in these patients. Given the known toxicities of RTIs, it is premature to recommend them to individuals at risk or with Alzheimer's disease who do not have HIV infection.

The relationship between synaptodendritic neuropathology and HIV-associated neurocognitive disorders is moderated by cognitive reserve.

We examined whether cognitive reserve moderated the relationship between neurodegeneration and cognition in 67 postmortem persons with HIV (PWH) who were cognitively assessed within 1 year of death. Cognitive reserve was measured via the Wide Range Achievement Test-4 reading subtest (WRAT4). Synaptodendritic neurodegeneration was based on densities of synaptophysin and microtubule-associated protein 2 immunohistochemical reactivity in frontal cortex, and categorized as minimal, moderate, or severe (tertile-split). T-Scores from 15 cognitive tests were averaged into a global cognitive T-score. Among those with low cognitive reserve (based on WRAT4 median split), the moderate neurodegeneration group showed cognition that was poorer than the minimal neurodegeneration group and comparable to the severe neurodegeneration group. Among those with high cognitive reserve, the moderate neurodegeneration group showed cognition comparable to the minimal neurodegeneration group and better than the severe neurodegeneration group. High cognitive reserve may buffer against cognitive impairment among PWH with moderate, but not severe, neurodegeneration.

GPR120/FFAR4 stimulation attenuates airway remodeling and suppresses IL-4- and IL-13-induced airway epithelial injury via inhibition of STAT6 and Akt.

BACKGROUND: Airway remodeling is associated with severity and treatment insensitivity in asthma. This study aimed to investigate the effects of G protein-coupled receptor 120 (GPR120) stimulation on alleviating allergic inflammation and remodeling of airway epithelium. RESEARCH DESIGN AND METHODS: Ovalbumin (OVA)-challenged BALB/c mice and type-2-cytokine (IL-4 and IL-13)-exposed 16HBE human bronchial epithelial cells were treated with GSK137647A, a selective GPR120 agonist. Markers of allergic inflammation and airway remodeling were determined. RESULTS: GSK137647A attenuated inflammation and mucus secretion in airway epithelium of OVA-challenged mice. Stimulation of GPR120 in 16HBE suppressed expression of asthma-associated cytokines and cytokine-induced expression of pathogenic mucin-MUC5AC. These effects were abolished by co-treatment with AH7614, a GPR120 antagonist. Moreover, GPR120 stimulation in 16HBE cells reduced expression of fibrotic markers including fibronectin protein and ACTA2 mRNA and inhibited epithelial barrier leakage induced by type-2 inflammation via rescuing expression of zonula occludens-1 protein. Furthermore, GPR120 stimulation prevented the cytokine-induced airway epithelial remodeling via suppression of STAT6 and Akt phosphorylation. CONCLUSIONS: Our findings suggest that GPR120 activation alleviates allergic inflammation and remodeling of airway epithelium partly through inhibition of STAT6 and Akt. GPR120 may represent a novel therapeutic target for diseases associated with remodeling of airway epithelium, including asthma.

Alzheimer-type cerebral amyloidosis in the context of HIV infection: implications for a proposed new treatment approach.

Reverse transcriptase inhibitors (RTIs) are currently broadly prescribed for the treatment of HIV infection but are also thought to prevent Alzheimer's Disease (AD) progression by protecting against amyloidosis. Our study evaluates the hypothesis that reverse transcriptase inhibitors protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection. We compiled a case series of participants from a prospective study of the neurological consequences of HIV infection at the HIV Neurobehavioral Research Program (HNRP) who had serial neuropsychological and neurological assessments and were on RTIs. Two participants had gross and microscopic examination and immunohistochemistry of the brain at autopsy; one was assessed clinically for Alzheimer's Disease by cerebrospinal fluid (CSF) analysis of phosphorylated-Tau, Total-Tau and Aß42. Additionally, a larger cohort of autopsied individuals was evaluated for presence of amyloid plaques, Tau, and related pathologies. Three older, virally suppressed individuals with HIV who had long-term treatment with RTIs were included in analyses. Two cases demonstrated substantial cerebral amyloid deposition at autopsy. The third case met clinical criteria for AD based on a typical clinical course and CSF biomarker profile. In the larger cohort of autopsied individuals, the prevalence of cerebral amyloidosis among people with HIV (PWH) was greater for those on RTIs. Our study showed that long-term RTI therapy did not protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection in these patients. Given the known toxicities of RTIs, it is premature to recommend them to individuals at risk or with Alzheimer's disease who do not have HIV infection.

Alzheimer's Disease Pathology in Middle Aged and Older People with HIV: Comparisons with Non-HIV Controls on a Healthy Aging and Alzheimer's Disease Trajectory and Relationships with Cognitive Function.

We determined the prevalence of Alzheimer's disease (AD) pathological hallmarks, amyloid-ß and phosphorylated-Tau, in autopsied brains of 49 people with HIV (PWH) (ages: 50-68; mean age = 57.0) from the National NeuroAIDS Tissue Consortium and in a comparative cohort of 55 people without HIV (PWoH) from the UC San Diego Alzheimer's Disease Research Center (17 controls, 14 mild cognitive impairment, 24 AD; ages: 70-102, mean age = 88.7). We examined how AD pathology relates to domain-specific cognitive functions in PWH overall and in sex-stratified samples. Amyloid-ß and phosphorylated-Tau positivity (presence of pathology of any type/density) was determined via immunohistochemistry in AD-sensitive brain regions. Among PWH, amyloid-ß positivity ranged from 19% (hippocampus) to 41% (frontal neocortex), and phosphorylated-Tau positivity ranged from 47% (entorhinal cortex) to 73% (transentorhinal cortex). Generally, AD pathology was significantly less prevalent, and less severe when present, in PWH versus PWoH regardless of cognitive status. Among PWH, positivity for AD pathology related most consistently to memory-related domains. Positivity for p-Tau pathology related to memory-related domains in women with HIV only, although the sample size of women with HIV was small (n = 10). Results indicate that AD pathology is present in a sizable portion of middle aged and older PWH, although not to the extent in older PWoH. Studies with better age-matched PWoH are needed to examine the effect of HIV status on AD pathology.

Behavioral and histological assessment of a novel treatment of neuroHIV in humanized mice.

Neurocognitive deficits are prevalent among people living with HIV, likely due to chronic inflammation and oxidative stress in the brain. To date, no pharmaceutical treatments beyond antiretroviral therapy (ARV) has been shown to reduce risk for, or severity of, HIV-associated neurocognitive disorder. Here we investigate a novel compound, CDDO-Me, with documented neuroprotective effects via activation of the nrf2 and inhibition of the NFkB pathways. Methods: We conducted three studies to assess the efficacy of CDDO-Me alone or in combination with antiretroviral therapy in humanized mice infected with HIV; behavioral, histopathological, and immunohistochemical. Results: CDDO-Me in combination with ARV rescued social interaction deficits; however, only ARV was associated with preserved functioning in other behaviors, and CDDO-Me may have attenuated those benefits. A modest neuroprotective effect was found for CDDO-Me when administered with ARV, via preservation of PSD-95 expression; however, ARV alone had a more consistent protective effect. No significant changes in antioxidant enzyme expression levels were observed in CDDO-Me-treated animals. Only ARV use seemed to affect some antioxidant levels, indicating that it is ARV rather than CDDO-Me that is the major factor providing neuroprotection in this animal model. Finally, immunohistochemical analysis found that several cellular markers in various brain regions varied due to ARV rather than CDDO-Me. Conclusion: Limited benefit of CDDO-Me on behavior and neuroprotection were observed. Instead, ARV was shown to be the more beneficial treatment. These experiments support the future use of this chimeric mouse for behavioral experiments in neuroHIV research.

Nephroprotective potential of Panduratin A against colistin-induced renal injury via attenuating mitochondrial dysfunction and cell apoptosis.

Colistin is a last-resort polypeptide antibiotic widely used to treat against multidrug-resistant Gram-negative bacterial infections. However, this treatment is associated with nephrotoxicity. The aim of this study was to examine the potential protective effect of panduratin A, a bioactive compound of Boesenbergia rotunda, on colistin-induced nephrotoxicity in both in vivo and in vitro models. Intraperitoneal injection of 15 mg/kg colistin for 7 days markedly promoted renal tubular degeneration, increased blood urea nitrogen (BUN) levels, and upregulated the expression of renal injury biomarker and apoptosis proteins. In addition, treatment with colistin increased oxidative stress and apoptosis in mice kidney tissues. Interestingly, these defects were attenuated when co-administered of colistin with panduratin A (2.5 or 25 mg/kg). The underlying mechanisms of panduratin A attenuating colistin toxicity was investigated in human renal proximal tubular cells (RPTEC/TERT1). The mechanisms by which colistin-triggered cytotoxicity was determined by analysis of cell death, reactive oxygen species (ROS) levels, mitochondria function as well as the expression of proteins related to apoptosis pathway. Colistin treatment (200 µg/ml) significantly increased cell apoptosis, elevated ROS production, reduced mitochondrial membrane potential, and decreased anti-apoptotic protein (Bcl-2) expression. These effects were notably suppressed by co-treatment with panduratin A (5 µM). Collectively, panduratin A exerts as a novel nephroprotective agent to protect against colistin-induced renal injury by attenuating mitochondrial damage and renal cell apoptosis.

CSF markers of AD-related pathology relate specifically to memory impairment in older people with HIV: a pilot study.

Given the co-occurrence of memory impairment in HIV-associated neurocognitive disorders (HAND) and amnestic mild cognitive impairment/Alzheimer's disease (aMCI/AD), biomarkers are needed that can disentangle these conditions among people with HIV (PWH). We assessed whether cerebrospinal fluid (CSF) markers of AD could help in this effort by determining their relationship to learning and memory deficits versus cognitive deficits more characteristic of HAND than aMCI/AD (processing speed and complex visual/motor coordination) among 31 older PWH. CSF amyloid-ß42 phosphorylated-tau, amyloid-ß40/amyloid-ß42 and phosphorylated-tau/amyloid-ß42 ratio related to learning/memory performance but not HAND-related deficits, suggesting that these biomarkers may have utility in disentangling aMCI/AD from HAND.

Antiretroviral Tenofovir Induces Senescence-Associated ß-Galactosidase Activity in Primary Human Brain Vascular Cells in Multi-Layer Three-Dimensional Co-Culture.

Introduction In the current context of early diagnosis of HIV infection, immediate initiation of antiretroviral (ARV) therapy, and lifelong chronic treatment, the potential ARV toxicity is of particular concern. Emtricitabine (FTC) and tenofovir (TFV) are commonly used as backbone drugs in ARV regimens recommended for initial therapy of HIV infection. Here we assessed the effects of FTC and TFV exposure on senescence-associated ß-galactosidase (SA-ß-Gal) activity, a marker of cellular senescence, in human brain vascular cells. Design Multi-layer three-dimensional cell co-cultures and in vitro assays. Methods To mimic the small vessel wall structure in vivo, three types of primary human brain vascular cells (endothelial cells, smooth muscle cells, and pericytes) were co-cultured on three Alvetex Scaffold disks placed on top of each other in order (three-layer three-dimensional cell co-cultures) and exposed to clinically relevant concentrations of ARV drugs (FTC, TFV, or FTC+TFV combination) or vehicle for eight days (four or five biological replicates per condition, 18 replicates totally). The SA-ß-Gal activity was quantitatively assayed in vitro by using the chemiluminescent Galacto-Star System (T1012; Applied Biosystems, Thermo Fisher Scientific, Waltham, MA) in 54 protein lysates extracted from individual cell-culture disks. Three-factor analysis of variance (cell type, FTC, TFV) was used to assess differences in the SA-ß-Gal activity levels normalized by the corresponding total protein concentrations. Results There was a trend for the FTC by TFV interaction effect on SA-ß-Gal activity (P = 0.058). The effects of FTC and TFV were not significantly different among the three cell types. The overall effect of FTC was not significant when controlling for TFV and cell type. The overall effect of TFV was significant when controlling for FTC and cell type (F(1,48) = 30.61, P < 0.001, partial η2 = 0.389). In the absence of FTC, TFV raised SA-ß-Gal activity by 0.631 units on average, regardless of cell type (P < 0.001, partial η2 = 0.368). In the presence of FTC, TFV raised SA-ß-Gal activity by 0.303 units on average, regardless of cell type (P = 0.015, partial η2 = 0.118). Conclusion Our preliminary findings suggest that primary human brain vascular cells exposed to TFV at clinically relevant concentrations undergo cellular senescence. This potential adverse effect of TFV should be further studied in animal models of HIV infection.

Distinguishing Amnestic Mild Cognitive Impairment From HIV-Associated Neurocognitive Disorders.

BACKGROUND: Memory impairment occurs in human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) and amnestic mild cognitive impairment (aMCI), the precursor to Alzheimer disease (AD). Methods are needed to distinguish aMCI-associated from HAND-associated impairment in people with HIV (PWH). We developed a neuropsychological method of identifying aMCI in PWH and tested this by relating AD neuropathology (ß-amyloid, phospho-Tau) to aMCI versus HAND classification. METHODS: Seventy-four HIV-positive cases (aged 50-68 years) from the National NeuroAIDS Tissue Consortium had neurocognitive data within 1 year of death and data on ß-amyloid and phospho-Tau pathology in frontal brain tissue. High aMCI risk was defined as impairment (<1.0 SD below normative mean) on 2 of 4 delayed recall or recognition outcomes from a verbal and nonverbal memory test (at least 1 recognition impairment required). Differences in ß-amyloid and phospho-Tau by aMCI and HAND classification were examined. RESULTS: High aMCI risk was more common in HAND (69.0%) versus no HAND (37.5%) group. ß-amyloid pathology was 4.75 times more likely in high versus low aMCI risk group. Phospho-Tau pathology did not differ between aMCI groups. Neither neuropathological feature differed by HAND status. CONCLUSIONS: Amnestic mild cognitive impairment criteria that include recognition impairment may help to detect AD-like cognitive/biomarker profiles among PWH.

Antiretroviral drug concentrations in brain tissue of adult decedents.

OBJECTIVE: Determine concentrations of antiretroviral therapy (ART) drugs in the human brain. DESIGN: Cohort study of persons with HIV who consented to antemortem assessment and postmortem autopsy. METHODS: Eleven persons with HIV who were taking ART at the time of death and had detectable concentrations of at least one ART drug in intracardiac aspirate at autopsy were evaluated. Autopsies were performed within 24 h of death and brain tissue was stored at -80 °C. Concentrations of 11 ART drugs were measured in three brain regions (globus pallidus, cortical gray matter, white matter) by HPLC tandem mass spectrometry with a lower limit of quantification of 25 ng/ml. RESULTS: Participants were mostly men (82%) with a mean age of 40.4 years. Drug concentrations in brain tissue were highly variable and exceeded published concentrations in cerebrospinal fluid for several drugs, including for tenofovir, efavirenz, and lopinavir. Drug concentrations correlated most strongly between cortical gray matter and globus pallidus (rho = 0.70) but less well between globus pallidus and white matter (rho = 0.43). Combining all drugs and brain regions (n = 89), higher drug concentrations in brain were associated with longer estimated duration of HIV infection (P = 0.015), lower HIV RNA in plasma (P = 0.0001), lower nadir CD4 T-cell count (P = 0.053), and worse neurocognitive performance (P = 0.017). CONCLUSION: This is the first analysis of ART drug concentrations in human brain tissue. Concentrations of several drugs in this analysis were similar to published concentrations in cerebrospinal fluid but others exceeded published concentrations. The association between higher drug concentrations in the brain and worse neurocognitive performance may indicate ART neurotoxicity.

Correction to: A candidate gene study of intermediate histopathological phenotypes in HIV-associated neurocognitive disorders.

Due to a production error data in Table 1 were not presented correctly.

A candidate gene study of intermediate histopathological phenotypes in HIV-associated neurocognitive disorders.

HIV-associated neurocognitive disorders (HAND) describe a spectrum of neuropsychological impairment caused by HIV-1 infection. While the sequence of cellular and physiological events that lead to HAND remains obscure, it likely involves chronic neuroinflammation. Host genetic markers that increase the risk for HAND have been reported, but replication of such studies is lacking, possibly due to inconsistent application of a behavioral phenotype across studies. In the current study, we used histopathologic phenotypes in order to validate putative risk alleles for HAND. The National NeuroAIDS Tissue Consortium, a longitudinal study of the neurologic manifestations of HIV. Data and specimens were obtained from 175 HIV-infected adults. After determining several potential covariates of neurocognitive functioning, we quantified levels of six histopathological markers in the frontal lobe in association with neurocognitive functioning: SYP, MAP 2, HLA-DR, Iba1, GFAP, and ß-amyloid. We then determined alleles of 15 candidate genes for their associations with neurocognitive functioning and histopathological markers. Finally, we identified the most plausible causal pathway based on our data using a multi-stage linear regression-based mediation analysis approach. None of the genetic markers were associated with neurocognitive functioning. Of the histopathological markers, only MAP 2 and SYP were associated with neurocognitive functioning; however, MAP 2 and SYP did not vary as a function of genotype. Mediation analysis suggests a causal pathway in which presynaptic degeneration (SYP) leads to somatodendritic degeneration (MAP 2) and ultimately neurocognitive impairment. This study did not support the role of host genotype in the histopathology underlying HAND. The findings lend further support for synaptodendritic degeneration as the proximal underlying neuropathological substrate of HAND.

Loss of Immunohistochemical Reactivity in Association With Handling-Induced Dark Neurons in Mouse Brains.

The handling-induced dark neuron is a histological artifact observed in brain samples handled before fixation with aldehydes. To explore associations between dark neurons and immunohistochemical alterations in mouse brains, we examined protein products encoded by Cav3 (neuronal perikarya/neurites), Rbbp4 (neuronal nuclei), Gfap (astroglia), and Aif1 (microglia) genes in adjacent tissue sections. Here, dark neurons were incidental findings from our prior project, studying the effects of age and high-fat diet on metabolic homeostasis in male C57BL/6N mice. Available were brains from 4 study groups: middle-aged/control diet, middle-aged/high-fat diet, old/control diet, and old/high-fat diet. Young/control diet mice were used as baseline. The hemibrains were immersion-fixed with paraformaldehyde and paraffin-embedded. In the hippocampal formation, we found negative correlations between dark neuron hyperbasophilia and immunoreactivity for CAV3, RBBP4, and glial fibrillary acidic protein (GFAP) using quantitative image analysis. There was no significant difference in dark neuron hyperbasophilia or immunoreactivity for any protein examined among all groups. In contrast, in the hippocampal fimbria, old age seemed to be associated with higher immunoreactivity for GFAP and allograft inflammatory factor-1. Our findings suggest that loss of immunohistochemical reactivity for CAV3, RBBP4, and GFAP in the hippocampal formation is an artifact associated with the occurrence of dark neurons. The unawareness of dark neurons may lead to misinterpretation of immunohistochemical reactivity alterations.

Risk of developing cerebral ß-amyloid plaques with posttranslational modification among HIV-infected adults.

OBJECTIVES: Evidence of accelerated brain aging among HIV-infected adults argues for the increased risk of developing cerebral ß-amyloid (Aß) plaques. We compared the frequency of Aß plaque-bearing cases in our HIV cohort with that in a general cohort reported by Braak et al. We explored posttranslationally modified Aß forms (N3pE, E22P, phospho-Ser8) in plaques and E22P-Aß in the postmortem cerebrospinal fluid (CSF) in the HIV cohort. DESIGN: Clinicopathological study of HIV-infected adults. METHODS: To assess frontal Aß plaque deposition, we conducted immunohistochemistry for generic Aß (4G8) and three modified Aß forms. We determined CSF E22P-Aß levels by ELISA. RESULTS: We found 4G8-Aß plaques in 29% of 279 HIV-infected cases. Within the age range of 31-70 years, the frequency of 4G8-Aß plaque-bearing cases was higher in our HIV cohort (n = 273) compared with the general cohort (n = 1110) overall (29.3 vs. 25.8%) and across four age groups by decade (odds ratio 2.35, P < 0.0001). In HIV-infected cases with (n = 37) and without (n = 12) 4G8-Aß plaques, modified Aß forms occurred in order: N3pE, E22P, and phospho-Ser8. In CSF assays of HIV-infected cases with (n = 27; 17 focal, 10 widespread) and without (n = 11) 4G8-Aß plaques, the median E22P-Aß/Aß40 ratio was higher among cases with widespread plaques than in cases with focal or absent plaques (P = 0.047). CONCLUSION: Our findings suggest HIV-infected adults are at increased risk of developing cerebral Aß plaques. The occurrence of modified Aß forms in order suggests the progression stages of Aß plaque deposition. The potential for E22P-Aß as a CSF biomarker of cerebral Aß plaques should be investigated.

Clinical Correlates of Insulin Resistance in Chronic Schizophrenia: Relationship to Negative Symptoms.

Higher prevalence of physical comorbidity and premature mortality in persons with schizophrenia (PwS) results primarily from heightened cardiovascular and metabolic risks. The literature suggests that insulin resistance precedes the development of obesity, smoking, and use of antipsychotic medications, although these likely play a compounding role later in the course of the disorder. It is thus important to discover the clinical characteristics of PwS with high insulin resistance, as these individuals may represent an etiopathologically distinct subgroup with a distinct course and treatment needs. We conducted a cross-sectional study and compared insulin resistance between 145 PwS and 140 nonpsychiatric comparison (NC) participants, similar in age, sex, and race distribution. In addition, we examined correlates of insulin resistance in PwS. As expected, PwS had higher levels of insulin resistance [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)] and body mass index (BMI) compared to the NC participants. HOMA-IR in the PwS was most associated with negative symptoms, BMI, and non-White race/ethnicity. The mechanistic relationships between insulin resistance and negative symptoms in schizophrenia patients warrant further investigation, and future studies should examine outcomes of PwS with this cluster of physical and mental symptoms and determine how management of insulin resistance might improve health of these individuals.

Associations of regional amyloid-ß plaque and phospho-tau pathology with biological factors and neuropsychological functioning among HIV-infected adults.

With increasing age, the general population is increasingly vulnerable to the development of cerebral amyloid-ß (Aß) plaque and neuronal phospho-tau (p-tau) pathology. In HIV disease, prior studies of these neuropathologic changes were relatively limited. Here, we characterized Aß plaques and p-tau lesions by immunohistochemistry in relevant brain regions (prefrontal neocortex, putamen, basal-temporal neocortex, and hippocampus) of HIV-infected adults. We used multivariable logistic regression to predict regional Aß plaque or p-tau pathology based on demographic factors, apolipoprotein E (APOE) genotypes, HIV disease-related factors, and regional gliosis. We used multiple linear regression to predict T-scores in neuropsychological domains based on regional Aß plaque or p-tau pathology. We found that APOE ε4 alleles, older age, and higher plasma HIV-1 RNA predicted prefrontal Aß plaques (odds ratio (OR) 5.306, 1.045, and 0.699, respectively, n = 168). Older age predicted putamen Aß plaques (OR 1.064, n = 171). APOE ε4 alleles, hepatitis C virus seropositivity, and higher plasma HIV-1 RNA predicted hippocampus Aß plaques (OR 6.779, 6.138, and 0.589, respectively, n = 56). The p-tau lesions were sparse in the vast majority of affected cases. Lifetime substance use disorder and higher plasma HIV-1 RNA predicted putamen p-tau lesions (OR 0.278 and 0.638, respectively, n = 67). Older age and gliosis predicted hippocampus p-tau lesions (OR 1.128 and 0.592, respectively, n = 59). Prefrontal Aß plaques predicted lower speed of information processing (n = 159) and putamen Aß plaques predicted lower levels of attention and working memory (n = 88). Regional p-tau lesions were not significantly predictive of any neuropsychological domains. In conclusion, Aß plaque or p-tau pathology in different brain regions was predicted by different sets of biological factors. Aß plaques in prefrontal neocortex and putamen predicted poorer functioning in cognitive domains relevant to these brain regions. The absence of significant impact of regional p-tau lesions on neuropsychological functioning might be explained by the subthreshold burden of p-tau lesions.

Association of antiretroviral therapy with brain aging changes among HIV-infected adults.

OBJECTIVE: Antiretroviral therapy (ART) is currently recommended for all persons living with HIV (PLWH), regardless of their CD4 T-cell count, and should be continued throughout life. Nonetheless, vigilance of the safety of ART, including its neurotoxicity, must continue. We hypothesized that use of certain ART drugs might be associated with aging-related cerebral degenerative changes among PLWH. DESIGN: Clinicopathological study of PLWH who were using ART drugs at the last clinical assessment. METHODS: Using multivariable logistic regression, we tested associations between use of each specific ART drug (with reference to use of other ART drugs) and cerebral degenerative changes including neuronal phospho-tau lesions, ß-amyloid plaque deposition, microgliosis, and astrogliosis in the frontal cortex and putamen (immunohistochemistry), as well as cerebral small vessel disease (CSVD) in the forebrain white matter (standard histopathology), with relevant covariates being taken into account. The Bonferroni adjustment was applied. RESULTS: Darunavir use was associated with higher likelihood of neuronal phospho-tau lesions in the putamen [odds ratio (OR) 15.33, n = 93, P = 0.005]. Ritonavir use was associated with marked microgliosis in the putamen (OR 4.96, n = 101, P = 0.023). On the other hand, use of tenofovir disoproxil fumarate was associated with lower likelihood of ß-amyloid plaque deposition in the frontal cortex (OR 0.13, n = 102, P = 0.012). There was a trend toward an association between emtricitabine use and CSVD (OR 13.64, n = 75, P = 0.099). CONCLUSION: Our findings suggest that PLWH treated with darunavir and ritonavir may be at increased risk of aging-related cerebral degenerative changes.

A novel animal model for neuroinflammation and white matter degeneration.

Small interference RNA has been widely used to suppress gene expression. Three different short hairpin RNAs (shRNAs) against dopamine D1 receptor (Drd1), driven by mouse U6 promoter in self-complementary AAV8 vector (scAAV8), were used to silence mouse striatal Drd1 expression. Transduction of mouse striatum with all three scAAV8-D1shRNA viruses, but not the control scAAV8 virus, causes extensive neuroinflammation, demyelination, and axon degeneration. RNA interference is known to be coupled to the innate immune system as a host cell defense against virus infection. Activation of the innate immune system may play a causal role in the development of neuroinflammation and white matter degeneration, providing a novel animal model for multiple sclerosis (MS) and other neuroinflammatory diseases.

Plasma soluble CD163 is associated with postmortem brain pathology in human immunodeficiency virus infection.

OBJECTIVE: Higher plasma soluble cluster of differentiation (CD)163 (sCD163), shed by monocytes and macrophages, correlates with neurocognitive impairment in HIV infection. We hypothesized that higher antemortem plasma or cerebrospinal fluid (CSF) sCD163 would be associated with greater postmortem neurodegeneration and/or microgliosis. DESIGN: Retrospective, postmortem observational study. METHODS: We measured sCD163 levels in antemortem plasma (n = 54) and CSF (n = 32) samples from 74 HIV-seropositive participants (median 5 months before death) who donated their brains to research at autopsy. Postmortem, we quantified markers of synaptodendritic damage (microtubule-associated protein 2, synaptophysin), microgliosis [human leukocyte antigen DR (HLA-DR), ionized calcium-binding adaptor molecule 1], astrocytosis (glial fibrillary acidic protein), and impaired protein clearance (ß-amyloid) in frontal cortex, hippocampus, putamen, and internal capsule. Multivariable least-squares regression was used to evaluate the association between plasma or CSF sCD163 and histological measures, correcting for multiple comparisons. RESULTS: Higher plasma sCD163 was associated with lower microtubule-associated protein 2 in frontal cortex [B = -0.23, 95% confidence interval (CI) -0.41 to -0.06, P = 0.04], putamen (B = 0.32, 95% CI -0.52 to -0.12, P = 0.02), and hippocampus (B = -0.23, 95% CI -0.35 to -0.10, P = 0.01), and with lower synaptophysin in hippocampus (B = -0.25, 95% CI -0.42 to -0.03, P = 0.02) but not putamen or frontal cortex (P > 0.05). Higher plasma sCD163 was associated with higher HLA-DR in putamen (B = 0.17, 95% CI 0.08 to 0.26, P = 0.008). CSF sCD163 was not associated with any histological measure (P > 0.05). CONCLUSION: Higher plasma sCD163 in life is associated with greater synaptodendritic damage and microglial activation in cortical and subcortical brain regions.